SUMMARY. The human immunodeficiency viruses (HIV-1 and HIV-2) are the result of multiple cross-species transmissions of simian lentiviruses into the human population from nonhuman, old world primates. Similarly, macaque isolates of simian immunodeficiency virus (SIVmac) arose initially by accidental cross-species transmission from an African monkey species into an Asian species, and experimental infection of Asian macaques with clonal SIVsm, SIVmac and HIV-2 isolates, results in a broad range of outcomes. In Africa, more than two-dozen primate species are also endemically infected with simian immunodeficiency viruses. Unlike humans and Asian macaques, infection in these natural hosts rarely results in pathogenic outcome. Host genetic variation manifests at multiple levels, influencing the movement of lentiviruses between species, giving rise to species-level differences in pathogenic outcome and (within species or populations) resulting in individual-to-individual variation in susceptibility to infection, rates of disease progression and severity of pathogenesis. In the HIV/AIDS field two loci, APOBEC3 and TRIM5, have been identified as encoding intrinsic barriers to cross-species transmission of lentiviruses between humans and other primate species. We discovered that the TRIM5 loci of old world monkeys, including multiple species of high relevance to AIDS research, are highly polymorphic. Common alleles of rhesus TRIM5[unreadable] display differential ability to restrict a variety of lentiviruses. Moreover, we have discovered a TRIM5-CypA variant in Asian macaques that does not restrict HIV-1, but which can restrict a variety of other lentiviruses. Cataloguing and understanding host genetic variation has the potential to impact HIV/AIDS research in several areas, including identification of new therapeutic regimens, improved animal models and clearer interpretation of results from clinical trials. The study of genes that influence susceptibility to lentiviral infection will also illuminate the processes that govern patterns of susceptibility to cross-species/zoonotic transmission and species-specific differences in pathogenic outcome. The experiments described in this proposal will take advantage of naturally occurring genotypic and phenotypic variation to establish biological relevance of endogenously expressed post-entry restriction, and to ascertain the potential of genetically encoded restriction factors to impact cross-species transmission of primate lentiviruses.